Transplanting neural progenitors to build a neuronal relay across the injured spinal cord.

Abstract

Cellular transplantation for repair of spinal cord injury is a promising therapeutic strategy that includes the use of a variety of neural and non-neural cells isolated or derived from embryonic and adult tissue as well as embryonic stem cells and induced pluripotent stem cells. In particular, transplants of neural progenitor cells (NPCs) have been shown to limit secondary injury and scar formation and create a permissive environment in the injured spinal cord through the provision of neurotrophic molecules and growth supporting matrices that promote growth of injured host axons. Importantly, transplants of NPC are unique in their potential to replace lost neural cells – including neurons, astrocytes, and oligodendrocytes – critical for reconstruction of the normal microenvironment of the spinal cord and restoration of connectivity and function. Different NPC preparations have been used for transplantation experiments in multiple, diverse models of SCI, ranging from the classical work with fetal spinal cord (FSC) that defined the optimal age for donor tissue and its capacity to generate neural cells (Reier et al., 1983; Reier et al., 1986), to studies that demonstrated the formation of a neuronal relay by NPC transplants across the injured spinal cord to reconnect the interrupted sensory system (Bonner et al., 2011). At the developmental stage of embryonic day (E)13.5–14 the FSC is composed primarily of neuronal restricted progenitors (NRP) and glial restricted progenitors (GRP), but also contains a small number of immature neural stem cells, neurons, endothelial cells and fibroblasts (Kalyani et al., 1998; Cai et al., 2002; Lepore and Fischer, 2005; Medalha et al., 2014). While grafts of acutely isolated FSC contain all of these cell subpopulations, the process of isolating and culturing of NRP and GRP from FSC, particularly by adherent, sub-confluent culture on a poly-L-lysine/laminin substrate generates pure, defined, and reproducible populations of progenitors (Cai et al., 2002) for cryopreservation or transplantation experiments. NRP and GRP, in contrast to multipotent NSC have a capacity for self-renewal and a restricted differentiation potential, as they are committed to neuronal and glial phenotypes, respectively (Han et al., 2002; Lepore and Fischer, 2005). The injured spinal cord, however, presents a variety of impediments not only to the regeneration of injured host axons in the form of chondroitin sulfated proteoglycans (CSPG) and myelin-associated byproducts, but also significantly limits the survival and differentiation of graft-derived neurons (Cao et al., 2002; Lepore and Fischer, 2005).